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BROAD SPECTRUM ANTIBIOTICS AND MISCELLENOUS ANTIBACTERIAL AGENTS Akinola Olugbenga. PhD Broad-spectrum antibiotics are a class of antibiotics that act against an extensive range of disease-causing bacteria by targeting both gram-positive and gram-negative bacterial groups. They are ofte...

BROAD SPECTRUM ANTIBIOTICS AND MISCELLENOUS ANTIBACTERIAL AGENTS Akinola Olugbenga. PhD Broad-spectrum antibiotics are a class of antibiotics that act against an extensive range of disease-causing bacteria by targeting both gram-positive and gram-negative bacterial groups. They are often grouped by their abilities to act upon the different bacterial groups. Doxycycline, Minocycline, Aminoglycosides, Ampicillin, Amoxicillin/clavulanic acid (Augmentin), Microlide antibiotics (Azithromycin, erythromycin), Carbapenems (e.g. imipenem), Piperacillin/tazobactam, Quinolones (e.g. ciprofloxacin), Tetracyclines, Chloramphenicol, Ticarcillin. TETRACYCLINES  STRUCTURE OF TETRACYCLINE STRUCTURE OF TETRACYCLINE TETRACYCLINES have a ring structure: FOUR-CYCLIC-ANTHRACYCLIN  TETRACYCLINE ❖It is a BROAD-SPECTRUM BACTERIOSTATIC ANTIBIOTIC. They affect rapidly multiplying organisms ❖Obtained from soil actinomycetes. ❖Slightly bitter & weakly water soluble.  CLASSIFICATION OF TETRACYCLINE: GROUP 1: Shorter Acting (t1/2 =6-10 hours) Tetracycline, Chlortetracycline, Xytetracycline GROUP 2: Intermediate Acting(t1/2=12-13 hours) Demeclocycline, Methacycline GROUP 3: Long Acting(t1/2=18-20 hours) Doxycycline, Minocycline  Pharmacodynamics: ❖ The carrier involved in the active transport of tetracycline's are absent in the mammalian 60S/40S cellular ribosomal units, hence they cannot damage host but selectively toxic to the microorganisms only. ❖ In Gram positive bacteria's – tetracycline's enter the cytoplasm by an energy-dependent active transport system, once inside the bacterial cell, tetracycline's inhibit the bacterial protein synthesis by binding to their 30S ribosomal subunit and blocking the attachment of t-RNA & m-RNA resulting in the peptide chain growth failure. ❖ In Gram negative bacteria's - tetracyclines enter the outer membrane by passive diffusion through their pore channels.  Pharmacokinetics: ❖Tetracycline'sare absorbed from GIT with variable bioavailability ❖Tetracycline's are widely distributed except C.S.F. ❖ Cross placental barrier and excreted in the milk. ❖Tetracycline'sare readily deposited in teeth, bones and tumours. ❖Dairy products, antacids & iron preparation's impair tetracycline's absorption either by chelation/altering the gastric PH except doxycycline and minocycline.  Pharmacokinetics: ❖Tetracycline induces the action of Phenytoin, Warfarin, & Chlorpropamide ❖Metabolized in the liver to form conjugated glucuronides, concentrated in bile (EHC) and excreted in urine (GF), except doxycycline and minocycline. ❖In renal impairment needs dose adjustment for long acting tetracycline's except Doxycycline.  Anti Microbial spectrum: HIGHLY ACTIVE Rickettsia, Chlamydia Psittaci, Chlamydia Trachomatis , Chlamydia Pneumoniae. HIGHLY Spirochete's like - Borrelia burgdorferi, Borrelia EFFICACIOUS recurrentis. HIGHLY Atypical pathogen like SENSITIVE -Mycoplasma pneumoniae, -Ureaplasma urealyticum. Gram-negative bacilli like – Vibrio Cholerae,Brucella abortus, Helicobacter pylori, Yersinia pestis, Actinomyces israeli,Francisella tularensis. They are also useful in the treatment of intestinal ameobiasis and trychomonas vaginalis  RESISTANCE : There are four mechanisms by which an organism develops resistance to tetracycline's- ❖Decreased cell permeability of the drug. ❖Increased drug efflux from bacteria by energy- dependant process. ❖Initiation of ribosomal protection which results in decreased affinity for the drug by ribosomes binding sites. ❖Enzymatic inactivation of the drug. Almost all gram-positive and gram-negative cocci and gram negative bacilli have become resistant. Some gram positive bacilli are inhibited without clinical benefit.  CONTRA INDICATIONS: Renal impairment Hepatic insufficiency Pregnancy Lactation in Children’s less than 10years of age. Intraathecial injections should be avoided. 12/14/2012 10  Precautions During pregnancy and lactation Avoided in patients on diuretics Renal/hepatic insufficiency Avoid preparation beyond expiry date Do not mix injectable TC with penicillin- inactivation occurs. Do not inject tetracycline's Intra-thecally. 12/14/2012 12  Side effects 1. Epigastric Distress 2. Diarrhoea 3. Impairment of bone development and decoloration of teeth. 4. Photosensitization and allergic reactions e.g intracranial hypertension  ADVERSE EFFECTS: ROUTE OF ADVERSE EFFECTS ADMINISTRATION ORAL ADMINISTRATION Nausea, Vomiting, Epigastric burning, diarrhoea, Stomatitis, Chronic fungal Esophagitis, Inhibit intestinal flora. I.V. ADMINISTRATION Thrombophlebitis. I.M. ADMINISTRATION Painful local irritation OINTMENTS Painful local irritation & sensitization. CHRONIC Super infections, Stomatitis, Chronic fungal esophagitis, ADMINISTRATION temporary suppression of bone growth, Staining of teeth, Headache, Pseudotumour cerebri,Vestibular toxicity, Anti-anabolic effects, Minocycline photosensitivity, Hepatotoxicity in pregnancy, Cumulative renal toxicity in impaired renal functions,Demeclocycline  CHLORAMPHENICOL ❖ Chloramphenicol is active against a wide range of Gram- negative organisms, Gram positive organisms and serious anaerobic infection. ❖ Chloramphenicol is used topically for treating conjunctivitis and external ear infections. ❖ Chloramphenicol was earlier drug of choice for typhoid fever. ❖ It is bacteriostatic.  Pharmacodynamics: ❖Chloramphenicol is bacteriostatic in low doses and bactericidal in high doses. ❖MOA: inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. It inhibits the peptidyl transferase activity of bacteria ribosomes, binding to the A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal sub-unit. Chloramphenicol directly interferes with substrate binding ❖In Gram positive bacteria, it enters the cytoplasm by an energy-dependent active transport system, tetracycline's inhibit the bacterial protein synthesis by binding to 50S ribosomal subunit and blocking the attachment of t-RNA & m-RNA resulting in the peptide chain growth failure. ❖In Gram negative bacteria’s-enter the outer membrane by passive diffusion through pores.  Pharmacokinetics : ❖Chloramphenicol on oral administration rapidly and completely absorbed from GIT. ❖Chloramphenicol widely distributed throughout the body tissues and fluids including C.S.F. ❖Crosses placental barriers & alsopresent in breast milk. ❖Metabolized in the liver by Glucuronyl conjugation, concentrated in bile or excreted in urine. ❖Plasma half-life is 3-5 hours. ❖Paracetamol increases the bioavailability. ❖Chloramphenicol is a potent enzyme inhibitor, inhibits the metabolism of morphine, warfarin,..  Pharmacokinetics : it is extremely soluble. it remains unbound to plasma proteins. it has a large volume of distribution and penetrates well into various tissues. it is metabolized in the liver to chloramphenicol glucuronate which is inactive. it is excreted in the kidney unchanged  AntiMicrobial spectrum: HIGHLY Salmonella typhi, Haemophilus ACTIVE influenza, Neisseria meningitides, Streptococcus pneumonia, Penicillin-resistant Bacteroides fragilis. SENSITIVE Spirochetes', Rickettsia, Mycoplasma, Klebsiella, Chlamydia. It is not active against Psuedomonas aeruginosa or enterobacter species. May be used as second line treatment in the vent of tetracycline resistant cholera. Chloramphenicol remains the first choice in the treatment of staphylococcal brain abcesses  RESISTANCE : Three mechanisms by which a bacteria resistance to Chloramphenicol. ❖Decreased cell permeability of the drug. ❖Initiation of ribosomal protection which results in decreased affinity for the drug by ribosomes binding sites. this is achieved by evolving mutations on the 50S sub-units. ❖Production of R-plasmid as well as chromosomal mediated chloramphenicol acetyltransferase that metabolizes chloramphenicol to an inactive form. This is often initiated by the Cat gene which inactivates chloramphenicol by covalent linkage of one or two acetyl groups.  CONTRA INDICATIONS: Renal impairment, Hepaticinsufficiency, Pregnancy, Neonates, blood forming diseases.  ADVERSE EFFECTS: Chloramphenicol induces bone marrow depression and aplasia. SEVERE / Idiosyncratic Aplastic anaemia –It is unrelated to FATAL the dose has a genetic cause. Gray baby syndrome –neonates cannot conjugate chloramphenicol, slow GFR can lead to fatal neonatal toxicity. Super-infection. REVERSIBLE Dose related bone marrow depression when daily doses exceeds 3-4gram/day for more than 1-2weeks. Recovery after 3-6weeks of Discontinuation of treatment. IRRITABLE Nausea, Vomiting, Diarrhoea, Pain on injection. EFFECTS MICROLIDE ANTIBIOTICS Erythromycin, Azythromycin, Roxithromycin Spiramycin Clatithromycin Telithromycin (A ketolide) They are xterised by the possession of many lactone rings to which one or more deoxy sugars are attached. MECHANISM OF ACTION Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit causing the Suppression of RNA- dependent protein synthesis by inhibition of translocation of mRNA. Typically bacteriostatic activity but bactericidal at high concentrations susceptible organisms  sos sos "'--macrolide E 30S 30S ---! uA X X XX X X A0 U G C G A U C C C subunit uA 0 "--fX X XX X X A U G C G C G A U C C C subunit L' GI IjC I III IIIII I I I CI I I I C codon 1 codon 2 codon 3 codon 4 3 C A!jC1 C1 U1 G1 A1 I I I I I I I I I C jJ IIIIIIIIII 5 (I-MET/ (ARG) (GLY) (SER) 5' od 1 codo 2 codon 3 codon 4 codon S codon 6 codon 1 3' C::t"-rl. (f MET/ (ARG) (GLY) (SER) (PRO) (THR) ) (Stop) Stan) The macrolides bind reversibly to the 505 subunit of bacterial ribosomes.There is evidence that some prevent the transfer of the peptidyl tRNA from the A-site to the P-site,thus preventing the elongation of the polypeptide chain. @ Ii E c G o UC G C G G UCC CC C A C C UGA U A C JUUi lC lt lC A U G C G C G O A _ ,., (Qt I -' oeda1 O ood a n " "' -' ,_, I I ;r' 5' X X X X X X A U G C G C G G A U C C so mRt;A llllll Ill IIIIIIIll  SPECTRUM OF ANTIBACTERIAL ACTIVITY ✔ Macrolides are similar to penicillins regarding their spectrum of activity. ✔ They are effective against Penicillin-resistant strains. GRAM +VE GRAM +VE GRAM –VE GRAM -VE BACILLI COCCI BACILLI COCCI Streptococcus Bacilus anthracis, Nesseria Legionella pneumoniae, gonorrhoeae pneumophila Strepto. pyogens Listeria Moraxella Bordetella pertussis monocytogenes catarrhalis Staphylococci ( Clostridium tetani Bartonella henselae most or penicillin resistant species Haemophilus and these are now influenzae, h. ducreyi. macrolide resistant also) Campylobacter jejuni Helicobacter pylori  ACID FAST BACILLI SPIROCHETES MISCELLANEOUS Mycobacterium Treponema pallidum Mycoplasma kanasii pneumoniae Mycobacterium avium Ureaplasma intracellulare urealyticum Mycobacterium avium Chlamydia complex trachomatis Mycobacterium leprae Chlamydia pneumoniae Chlamydia psittaci  BACTERIAL RESISTANCE ✔ Methylation of a guanine residue on ribosomal RNA leads to lower affinity toward Macrolides ✔ An active efflux system ✔ Presence of a plasmid-associated erythromycin esterase PHARMACOKINETICS ABSORPTION ✔ERYTHROMYCIN – variableabsorption, food may decrease absorption. Enteric coated Esters and ester salts: more acid stable ✔CLARITHROMYCIN – acid stable and well-absorbed, regardless of presence of food. ✔AZITHROMYCIN –acid stable, food decreases absorption of capsules. DISTRIBUTION: ✔Extensive tissue and cellular distribution ✔Clarithromycin and Azithromycin with extensive penetration. ✔No BBB and CSF penetration ✔Erythromycin accumulates in the prostatic fluid and also in macrophages. ✔Azithromycin accumulates in Neutrophils, Macrophages, Fibroblasts. Has large volume of distribution and longest half life (greater than 40 hrs) ELIMINATION: ✔Clarithromycin is the only Macrolide partially eliminated by the Kidney(18% of parent and all metabolites). ✔Hepatically eliminated: ALL. ✔NONE of the macrolides are removed during hemodialysis ✔Erythromycin and Azithromycin are primarily concentrated and excreted through bile as active drugs.  Resistance ✔ Clarithromycin and Azithromycin show cross- resistance with Erythromycin, but Telithromycin can be effective against Macrolide-resistant organisms. ✔ Lack of cell wall permeability to Macrolides is the reason why G(-) bacteria are resistant to antibacterial effects of these agents. Administration and fate of the Macrolide antibiotics. ADVERSE EFFECTS GASTROINTESTINAL EFFECTS: ✔ Anorexia, nausea, vomiting, and diarrhoea occasionally accompany oral administration. ✔ Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most common reason for discontinuing Erythromycin and substituting another antibiotic. LIVER TOXICITY: ✔ Erythromycins particularly the,estolate an produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis reoccurs if the drug is re-administered ✔ Macrolides get deposited in perilymph and causes ototoxicity. ✔ Other allergic reactions include fever, eosinophilia, and rashes. ✔ Prolong QT Wave DRUG INTERACTIONS Erythromycin metabolites can inhibit P450 enzymes and thus increase the serum concentration of numerous drugs including theophylline, oral anticoagulants, cyclosporines and methyl prednisolone Erythromycin increases serum concentrations of oral Digoxin by increasing its bioavailability. THERAPEUTIC USES OF ERYTHROMYCIN It is used to treat a. The upper part of the respiratory tract infections, b. Soft tissue G(+) infections, c. Urethritis caused by MRSA, urealyticum d. Mycoplasma pneumonia caused by pneumonia, campylobacter jejuni e. Chlamydia infections Majorly C. Trachomatis - (may result in Urethritis, epididymitis, cervicitis, pelvic inflammatory disease (PID) and other conditions. ) C. Pneumonia – causes respiratory illness (prolonged cough, bronchitis, and pneumonia as well as a sore throat, laryngitis, ear infections, and sinusitis) f. Gonorrhoea caused by Nesseria gonorrhoea g. Treatment and prophylaxis of ophthalmic infections and also neonatal conjuctivitis h. To treat acne i. Pelvic inflammatory disease due to susceptible organisms (e.g., Streptococcus Pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Chlamydia, Legionella, Mycoplasma, Nesseria gonorrhoeae, Treponema) ADVERSE DRUG REACTIONS: ✔ Ventricular arrhythmias, QT interval prolongation ✔ Pseudomembranous colitis, ✔ Nausea/Vomiting, abdominal pain, cramping, diarrhea, hepatitis, rash, pruritis, phlebitis at IV site, allergic reactions. THERAPEUTIC USES Roxithromycin has same spectrum as of Erythromycin but it is more potent against moraxella catarrhalis and legionella and less potent against bordetella pertusis THERAPEUTIC USES OF SPIRAMYCIN It also resembles Erythromycin in its spectrum, though it has weaker activity. However, it is highly efficacious against toxaplasma gondii and cryptosporidium causes Watery diarrhoea with abdominal cramps. CLINICAL APPLICATIONS OF CLARITHROMYCIN ✔ It is used to treat Respiratory tract infections (pharyngitis/tonsillitis ). ✔ skin/skin structure infections due to susceptible organisms (e.g., S. pneumo, S. pyogenes, S. aureus, M. catarrhalis, Hemophilus influenza, Chlamydia pneumoniae, Mycoplasma). ✔ To prevent or treatment of disseminated MAC infection.(Anemia is common in patients with disseminated MAC disease) ✔ To Eradicate of H. pylori associated with peptic ulcer disease. ADVERSE DRUG REACTIONS : Hepatic failure, Pseudomembranous colitis, Stevens-Johnson syndrome, Toxic epidermal necrolysis, Drug rash (with eosinophilia)  THERAPEUTIC USES OF AZITHROMYCIN ✔ It has an extended spectrum compared to Erythromycin. ✔ It has a higher activity against trachomatis, Chlamydia Mycoplasma gonorrhoeae, pneumoniae, Nesseria toxoplasma gondii. ✔ Campylobacter jejuni (It is among the most common bacterial infections of humans, often a foodborne illness.) ✔ H. Influenza (Bacteremia , Meningitis,Epiglotittis, Cellulitis, Infectious arthritis). ✔ Moraxella catarrhalis (can cause infection of respiratory the system, middle ear, eye, central nervous system). ✔ It is used to acute bacterial infection ✔ Single dose treatment mild to moderate sinusitis ✔ Chancroid ( STD; Caused by haemophilus ducreyi) ✔ To treat nongonococcal infections (urethritis, cervicitis) ✔ Prevention or treatment of MAC infection in patients with advanced HIV. ADVERSE REACTIONS: ✔ Pseudomembranous colitis, ✔ Abdominal pain, Nausea /Vomiting, ✔ Rash